The primary objective of this project is to determine the mechanism of action of a series of afterload reducing agents (systemic vasodilators) which are currently being found to be of clinical importance for the treatment of heart failure. While it is well known that the benefit of afterload reducing agents in the treatment of heart failure is in their ability to reduce systemic vascular resistance, there is little or no information regarding the effect of these agents on specific vascular beds within the peripheral circulation. Furthermore, since heart failure of different etiologies can result in different peripheral compensatory mechanisms, it is highly likely that reduction of afterload by the vasodilators is achieved by means of different mechanisms in different forms of heart failure. Finally, since each afterload reducing agent is likely to achieve its effect by a slightly different mechanism, it is possible that the matching of certain vasodilators with certain forms of heart failure may have hazardous physiological consequences. In order to achieve the primary objective of this application, the effects of a series of different afterload reducing agents on parameters of cardiac function and peripheral blood flow to the specific regions of the circulation (radioactive microspheres) as well as on the total systemic cardiac output distribution will be determined in conscious rats, both in the resting state and during a treadmill exercise stress. In order to determine directly if different afterload reducing agents cause different effects depending upon the etiology of the heart failure condition, three models of heart failure in the rat will be studied; low output failure due to myocardial infarction by coronary artery ligation, low output failure due to myocardial disease secondary to radiation exposure, and high output failure due to chronic arterio-venous shunt. By these techniques, it will be possible to construct a unified concept relating the mechanisms of afterload reduction to the altered states of cardiac and peripheral vascular function which occur in the state of heart failure.